Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.

Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.

A single center experience on PI3K/AKT/MTOR signaling defects: Towards pathogenicity assessment for four novel defects.

BACKGROUND: Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia. OBJECTIVE: To characterize the PI3K/AKT/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity. METHODS: We included 12 patients (heterozygous PIK3CD (n = 9) and PIK3R1 (n = 1) (activated PI3K delta syndrome (APDS) with gain-of-function mutations) and homozygous PIK3R1 variant (n = 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. RESULTS: Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5-37) in APDS. Median diagnostic delay was 12.9 years (1.6-27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non-Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late-onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss-of function mutations. CONCLUSION: Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.

Evaluation of periodontal status and cytokine response in children with familial Mediterranean fever or systemic juvenile idiopathic arthritis.

OBJECTIVES: Familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) are chronic inflammatory diseases and anti-inflammatory agents are used in their treatment. This study evaluates the periodontal status and cytokine response in pediatric patients with FMF or sJIA. MATERIALS AND METHODS: Forty-eight FMF/sJIA patients were under treatment/control and in attack-free period; 20 systemically healthy children participated in the study. FMF/sJIA patients were divided into two subgroups based on the treatment they received: receiving anti-IL-1 therapy (anti-IL-1 ( +)) and not receiving anti-IL-1 therapy (anti-IL-1 ( -)). The clinical periodontal indices were recorded. Gingival crevicular fluid (GCF) and serum samples were collected. Cytokine levels (IL-1ß, IL-1α, TNF-α, IL-6, IL-8, IL-10, IL-17, IL-33) in GCF and serum were measured using ELISA kits. RESULTS: There was no significant difference between the groups in terms of GCF IL-1ß and IL-1α levels although, BoP and GI were significantly lower in the anti-IL-1 ( +) group compared to the control group. GCF IL-10 level was higher in the anti-IL-1 ( -) group than in the control group; GCF IL-8 levels were lower in both FMF/sJIA subgroups versus controls. There was no significant difference between serum cytokine levels of FMF/sJIA subgroups. CONCLUSIONS: Considering the significant decrease in GI, BoP, and GCF IL-8 levels in the anti-IL-1 ( +) group, it can be concluded that anti-IL-1 medications may suppress periodontal inflammation clinically and immunologically. CLINICAL RELEVANCE: Anti-IL agents are not currently used in periodontal therapy. However, this study demonstrated the positive effect of anti-IL-1 medications on periodontal inflammation in pediatric patients with FMF or sJIA.

Influence of video display terminal use and meibomian gland dysfunction on the ocular surface and tear neuromediators.

OBJECTIVE: To evaluate the effects of video display terminal (VDT) work and meibomian gland dysfunction (MGD) on ocular surface parameters, tear cytokine and substance P (SP) levels, and their association with dry eye disease (DED). METHODS: This cross-sectional study included 60 patients with evaporative DED and 20 healthy individuals. The DED patients were divided into three groups according to daily VDT work time and presence of MGD. The ocular surface and tear film were assessed using the Ocular Surface Disease Index questionnaire (OSDI), tear film break-up time (TBUT), ocular surface staining, Schirmer II test, and corneal sensitivity. MGD was evaluated with meibography. Corneal nerve alterations were evaluated using in vivo confocal microscopy (IVCM). The tear levels of 30 cytokines and SP were examined. RESULTS: Compared to controls, DED patients had higher OSDI score (p < 0.001), increased corneal staining with fluorescein and lissamine green (p = 0.046, p = 0,038), and lower TBUT (p < 0.001). Tear interleukin-6 levels were higher in DED patients, while tear SP levels did not differ between the groups (p = 0.265). VDT work time showed a weak positive correlation with OSDI (r = 0.274, p = 0.014) and SP level (r = 0.284, p = 0.011). CONCLUSION: The results of this study show that VDT use and MGD have an adverse effect on the ocular surface. It was also observed that the combination of VDT use and MGD did not significantly increase the ocular surface disease, but longer VDT exposure may be associated with more complaints of ocular discomfort.

A single-center study points to diverse features and outcome in patients with Hyperimmunoglobulin M Syndrome and Class- Switch Recombination defects.

Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n = 18), followed by CD40 Ligand (CD40L) (n = 14) and CD40 (n = 3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p = .001 and p = .008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p = .002 and 77.8%, p = .002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n = 4, CD40 deficiency n = 2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.

Adenosine Deaminase Type II Deficiency: Severe Chronic Neutropenia, Lymphoid Infiltration in Bone Marrow, and Inflammatory Features.

Deficiency of adenosine deaminase type 2 (DADA2) is an autoinflammatory disease characterized with immunologic, hematologic, and neurological features. Here, we presented two patients with severe persistent chronic neutropenia, which required differential diagnosis of congenital and autoimmune neutropenia, myelodysplastic syndrome (MDS), and primary immunodeficiency diseases, including autoimmune lymphoproliferative disease. The therapy of the disease except hematopoietic stem cell transplantation is a challenging experience.

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency.

BACKGROUND: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings. OBJECTIVE: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis. METHODS: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry. RESULTS: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia. CONCLUSIONS: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.

Clinical and Immunological Characteristics of 63 Patients with Chronic Granulomatous Disease: Hacettepe Experience.

BACKGROUND: Chronic granulomatous disease (CGD), one of the phagocytic system defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex which generates reactive oxygen species (ROS), which are essential for killing pathogenic microorganisms, especially catalase-positive bacteria and fungi. OBJECTIVE: The objective of our study was to assess the clinical and laboratory characteristics, treatment modalities, and prognosis of patients with CGD. METHODS: We retrospectively reviewed 63 patients with CGD who have been diagnosed, treated, and/or followed-up between 1984 and 2018 in Hacettepe University, Ankara, in Turkey, as a developing country. RESULTS: The number of female and male patients was 26/37. The median age at diagnosis was 3.8 (IQR: 1.0-9.6) years. The rate of consanguinity was 63.5%. The most common physical examination finding was lymphadenopathy (44/63), growth retardation (33/63), and hepatomegaly (27/63). One adult patient had squamous cell carcinoma of the lung. The most common infections were lung infection (53/63), skin abscess (43/63), and lymphadenitis (19/63). Of the 63 patients with CGD, 6 patients had inflammatory bowel disease (IBD). Twelve of the 63 patients died during follow-up. CYBA, NCF1, CYBB, and NCF2 mutations were detected in 35%, 27.5%, 25%, and 12.5% of the patients, respectively. CONCLUSION: We identified 63 patients with CGD from a single center in Turkey. Unlike other cohort studies in Turkey, due to the high consanguineous marriage rate in our study group, AR form of CGD was more frequent, and gastrointestinal involvement were found at relatively lower rates. The rate of patients who treated with HSCT was lower in our research than in the literature. A majority of the patients in this study received conventional prophylactic therapies, which highlight on the outcome of individuals who have not undergone HSCT.

Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey.

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.

Differential diagnosis of primary immunodeficiency in patients with BCGitis and BCGosis: A single-centre study.

BCG infections occur more frequently in patients with underlying primary immunodeficiency disease (PIDD). In this study, we aimed to evaluate the ratio of PIDD in the patients with BCG infections. Patients with BCG infections were analyzed in a tertiary referral centre in the 2015-2020 period. Forty-seven patients with BCGitis/BCGosis were evaluated; thirty-four (72.3%) had BCGitis, and 13 (27.7%) had BCGosis. Common tissue and organs affected are lymph nodes (57.4%), skin and subcutaneous tissue (48.9%), lungs (23.4%) and liver (17%). PIDD was shown in 26 patients (55.3%), including 92.3% of patients with BCGosis and 41.2% of patients with BCGitis. Ten patients had Mendelian susceptibility to Mycobacterial disease (MSMD) (21.2%), six had predominantly antibody deficiency (PAD) (12.7%), five had severe combined immunodeficiency (SCID) (10.6%), three had CGD (6.3%), and two had CID (4.2%). Mortality was reported in two patients (4.2%) with CID (ZAP70 deficiency (n = 1) and PIK3R1 deficiency (n = 1)). Parental consanguinity (84%), axillary lymphadenopathy (65%), mycobacterial lung disease (42%), hepatomegaly (30%) and growth retardation (19%) were significantly high in patients with PIDD diagnosis. Isolated vaccination site infection was also recorded in patients with PIDD (CID (n = 1), SCID (n = 1), PAD (n = 5)). BCG vaccination should be planned with caution for the cases with suspected PIDD. This study indicates that almost all patients (92.3%) with BCGosis and one in every two patients (41.2%) with BCGitis have an underlying PIDD. Parental consanguinity, axillary lymphadenopathy, mycobacterial lung disease, hepatomegaly and growth retardation (19%) are important clinical features in the differential diagnosis of PIDD.

Expression of HLA class I and class II genes in patients with multiple skin warts.

Human leukocyte antigens (HLAs), which are genetic markers that have critical roles in the immune response against pathogens, vary greatly among individuals. The aim of the study is to investigate the frequency of HLA class I (HLA-A, HLA-B and HLAC) and class II (HLA-DRB1, HLA-DQB1 and HLA-DQA1) genes in patients with multiple skin warts and to elucidate the role of these genes in the genetic susceptibility to skin warts. Peripheral venous blood samples were collected from 100 patients with multiple skin warts and 300 healthy individuals (controls). HLA typing was performed after DNA isolation from the blood samples. The HLA-A*02 (odds ratio [OR]: 0.12; p = 0.0019), HLA-DQA1*03:01 (OR: 0.45; p = 0.0017) and DQA1*05:01 (OR: 0.17; p < 0.0001) genes were significantly more prevalent in the patients than in the healthy individuals and were thus identified as risk genes. The HLA-DQA1*01:01 (OR: 0.17; p < 0.0001), HLA-DQA1*01:02 (OR: 0.17; p < 0.0001), HLA-DQA1*01:03 (OR: 0.11; p < 0.0001), HLA-DQA1*02:01 (OR:027; p<0.0001) and HLA-DQA1*05:05 (OR:0.16; p<0.0001) genes were classified as protective genes because of their low frequencies in the patients. The limitation of the study is that Human papillomavirus typing could not be performed while investigating the relationship between skin warts and HLA class I and class II genes. Our data suggest the role of HLA genes in the development of skin warts. However, other components of the major histocompatibility complex system and acquired factors of the immune system could also be involved and should be further investigated.

Frequency of HLA Class I and Class II Alleles in Patients with CVID from Turkey.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Certain gene loci are pointed out in several studies in CVID patients. Until now, monogenic defects have been identified in only 2-10% of CVID patients; therefore, association of the disease with HLA alleles may be important for elucidating immunological and genetic mechanisms behind CVID. The aim of this study is to investigate the relationship between CVID and HLA alleles. METHODS: HLA class I/II alleles were analyzed in 65 patients with CVID and alleles that may be related to disease susceptibility were determined by comparing with 300 healthy controls. We also evaluated HLA allele frequencies in CVID patients with gastrointestial system (GIS) involvement and autoimmune manifestations. RESULTS: When compared with controls, frequencies of B*27, B*35, C*04, and DRB1*04 alleles were significantly different in patients with CVID (p < .05). Frequencies of C*12, DRB1*13, and DRB1*15 alleles were more frequent in controls, indicating protective alleles (p < .05). There was a statistically significant difference for DQ2 and DQ8 haplotypes between patients with GIS involvement and controls. CONCLUSION: In comparison with literature, distinctive HLA alleles found in our study may originate from the diversity in gene pool between the populations. These data may provide clues for disease susceptibility.

Human Leucocyte Antigen Genotyping in Celiac Disease: Reasons for Inappropriate Use.

BACKGROUND: Celiac disease (CD) is an autoimmune enteropathy, which may need further Human Leukocyte Antigen (HLA) testing beyond autoantibodies for diagnosis due to the necessity of lifetime gluten restriction. HLA genotyping test is useful in certain scenarios for CD diagnosis and screening. The aim of this study was to evaluate the reasons for inappropriate requesting of HLA testing. METHODS: One hundred and fifteen patients, who had been tested for CD-related HLAs, were included in this study. Final diagnosis, indication of HLA test, serological and histopathological findings were re-evaluated to determine the inappropriate usage of HLA testing. RESULTS: Among all patients, 44 (38.2%) were diagnosed with CD according to their genotyping results. The frequency of DQ 2.5, DQ8 and DQ2.2 haplotypes among these patients was 57.2%, 28.2%, and 14.3%, respectively. HLA test was performed inappropriately in 35 (30.4%) of patients. The most common reason was serology and pathological findings of patients were already conclusive as CD in 15 (42.9%) patients. Serology negative patients were tested without any supporting finding of CD in 11 (31.4%) patients. Last identified reason was that patients whose serology and intestinal biopsy were not conclusive as CD in 9 (25.7%) patients. CONCLUSIONS: Before requesting HLA typing test, patient's data should be thoroughly evaluated to confirm the need for test.

Evaluation of periodontal status and cytokine/chemokine profile of GCF in patients with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a primary immunodeficiency characterized by defect in neutrophil count. Increased risk of infections in addition to periodontal problems, such as ulcerations of oral mucosa, gingival inflammation, and rapid loss of attachment are common in the course of the disease. The aim of the present study is to define the causal relationship between the severity of periodontal inflammation and severe congenital neutropenia through identification of cytokine profile in gingival crevicular fluid (GCF). A case-control study was performed in patients diagnosed with SCN and healthy controls. Demographic data, the molecular defect, laboratory work-up were gathered from the hospital registry. Periodontal indices were recorded and GCF samples were analyzed using multiplex analysis for the simultaneous measurements of the particular cytokines and chemokines. The present study included 14 patients and 22 control subjects. Both groups were comparable in terms of age and sex. Severity of gingival inflammation measured by the criteria of Löe was higher in the SCN cases (p < 0.05). Moreover, GCF levels of IFN-α, TNF-α, IL-10, IL-13, IL-15, IL-17, IL-2, IL-7, IL-33, IP-10, MIG, MIP-1ß were significantly higher in the controls. Decreased cytokine secretion seems to correlate with the decrease in neutrophil counts. The severity of gingival inflammation in SCN patients may be due to the bacterial overgrowth and the change in the content of the oral flora due to the decreased neutrophil counts. Therefore, regular periodontal examinations, the motivation of oral hygiene as well as the compliance with therapy in SCN patients contribute to the periodontal health.

Lymphocyte Subgroups and KREC Numbers in Common Variable Immunodeficiency: A Single Center Study.

Common variable immunodeficiency (CVID) results in defective B cell differentiation and impaired antibody production and is the most common symptomatic primary immunodeficiency. Our aim was to evaluate the correlation among B cell subgroups, κ-deleting recombination excision circle (KREC) copy numbers, and clinical and immunological data of the patients with CVID, and evaluate the patients according to classifications currently available to define the role of KREC copy numbers in the diagnosis of CVID. KREC analysis was performed using a quantitative real-time polymerase chain reaction assay, and B cell subgroups were measured by flow cytometry. The median age of the patients (n = 30) was 25 (6-69) years. Parental consanguinity ratio was 33%. The median age at diagnosis was 15 (4-59), and follow-up period was 6 (1-37) years. CD19+ and CD4+ cell counts at the time of diagnosis were low in 66.7% and 46.7% of the patients, respectively. CD19+ cell counts were positively correlated with KREC copy numbers in patients and healthy controls. CD19+ cell counts and KREC copy numbers were significantly reduced in CVID patients compared to healthy controls as expected. KRECs are quantitative markers for B cell defects. We found low CD4+ cell numbers, recent thymic emigrants, and lymphopenia in some of the patients at diagnosis, which reminds the heterogeneity of CVID's etiology. In this study, a positive correlation was shown between CD19+ cell counts and KREC copy numbers. Low KREC copy numbers indicated B cell deficiency; however, high KREC copy numbers were not sufficient to rule out CVID.

Levels of pro- and anti-inflammatory cytokines in cystic fibrosis patients with or without gingivitis.

BACKGROUND: Inflammatory periodontal diseases are caused by interaction between gram negative, anaerobic bacteria and host response. Persistent infection of Pseudomonas aeruginosa in cystic fibrosis (CF) patients also cause increased pro-inflammatory response and the imbalance of pro- and anti-inflammatory response in brochoalveolar lavage fluid which leads to destruction of lungs. The aim of this study is to evaluate periodontal status of CF patients, to measure level of cytokines and biochemical molecules in gingival crevicular fluid (GCF), and to detect presence of P. aeruginosa in dental plaque samples. MATERIALS AND METHODS: GCF samples were collected from 41 CF patients and 39 healthy (non-CF) subjects. Interleukin (IL)-1ß, IL-17, IL-10, human neutrophil elastase (HNE), cystic fibrosis transmembrane regulator (CFTR) protein, and human ß-defensin-1 (HBD1) in GCF were evaluated by ELISA method. Dental plaque samples were collected from 18 CF patients with history of P. aeruginosa colonization and 15 non-CF subjects. Presence of P. aeruginosa was evaluated by using conventional culture methods and molecular methods. RESULTS: Levels of IL-1ß, HNE, and HBD1 in CF patients were significantly higher than non-CF subjects. However, IL-10 level was significantly lower in CF patients. Increased pro-inflammatory (IL-1ß) and decreased anti-inflammatory (IL-10) cytokine levels were observed in GCF samples from CF patients, irrespective of their periodontal status. P. aeruginosa were detected in four samples of 18 CF patients, and all were negative in non-CF group. CONCLUSIONS: As a result of this study, CF coexists increasing pro-inflammatory and decreasing anti-inflammatory response locally. Due to increasing pro-inflammation, CF patients should be followed-up more often than non-CF children.

Elevated Interleukin-17A expression in amlodipine-induced gingival overgrowth.

BACKGROUND AND OBJECTIVES: Amlodipine, a calcium channel blocker derivative, is frequently used by patients with high blood pressure. Studies reported that it can induce gingival overgrowth. However, the underlying mechanism is not fully described yet. Interleukin-17A (IL-17A) is known as a proinflammatory cytokine, but current studies indicate that it has a role in fibrotic disorders and epithelial-mesenchymal transition (EMT). The aim of this study was to figure out the possible role of IL-17A in amlodipine-induced gingival overgrowth. MATERIALS AND METHODS: Twenty-nine (29) individuals participated in the study, and they were assigned into 3 groups based on medical status and clinical periodontal examination; 9 patients with amlodipine-induced gingival overgrowth, 11 patients with inflammatory gingival overgrowth, and 9 healthy individuals as a control group. Clinical periodontal parameters including plaque index (PI), gingival index (GI), and gingival overgrowth index (GOI) were recorded. Blood and gingival crevicular fluid (GCF) samples were obtained. Gingival tissues were taken by appropriate periodontal surgery following initial periodontal therapy. To detect IL-17A on tissue samples, immunohistochemistry (IHC) was performed. Quantitative analysis was done, and the expression level of IL-17A was given as the percent positively stained cells. Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze IL-17A in serum and GCF samples. RESULTS: All recorded clinical parameters were significantly higher in gingival overgrowth groups compared with control. Evaluation of inflammation on tissue sections did not show any significant change within the groups. Immunohistochemistry findings showed that IL-17A expression was increased in amlodipine samples (81.90%) compared with control samples (42.35%) (P < .001). There was an increase in the inflammatory group (66.08%) which is significantly less than the amlodipine group (P < .05). IL-17A levels in serum and GCF samples were not different within the study groups. CONCLUSION: In this study, elevated IL-17A expression regardless of inflammation shows that amlodipine might cause an increase of IL-17A in gingival tissues. This increase might induce fibrotic changes and EMT in gingival overgrowth tissues. The association of IL-17A with fibrosis and EMT in gingival tissues requires further investigation.

Recurrent Demyelinating Episodes as Sole Manifestation of Inherited CD59 Deficiency.

Defects in the regulatory components of the complement system can lead to inflammatory diseases. We present a patient who had four episodes of demyelination in the central nervous system as the only manifestation of inherited CD59 deficiency. Relapsing encephalopathy partially responsive to intravenous immunoglobulin and steroid treatments on the background of parental consanguinity suggested an inherited immune dysregulation. Next generation sequencing revealed homozygous mutation in the CD59 gene, confirmed by lack of CD59 expression on flow cytometry. Inherited CD59 deficiency is a rare autosomal recessive condition characterized by chronic hemolysis, recurrent strokes, and relapsing peripheral demyelinating neuropathy mimicking Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Recurrent central nervous system demyelinating episodes as the only manifestation has not been reported to date in inherited CD59 deficiency. This entity should be considered in the differential diagnosis of patients with early-onset recurrent neurological diseases with central or peripheral origin.

A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Evaluation of Long-Term Silicone Hydrogel Use on Ocular Surface Inflammation and Tear Function in Patients With and Without Meibomian Gland Dysfunction.

OBJECTIVES: To determine whether silicone hydrogel (SH) contact lens (CL) use, with or without meibomian gland dysfunction (MGD), promotes ocular surface inflammation. METHODS: Subjects wearing SH-CL for at least 6 months who also had coexisting MGD (group 1, n=20), SH-CL users who did not have MGD (group 2, n=20), patients who had MGD but did not use CL (group 3, n=20), and healthy CL-naive individuals with no known systemic or ocular diseases (group 4, n=20) were included in this cross-sectional, single-center study. All subjects underwent tear function tests consisting of tear break-up time (tBUT), ocular surface staining, Schirmer test, and the Ocular Surface Disease Index (OSDI) questionnaire, as well as determination of tear IL-1RA, IL-1ß, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IFN-α, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor, IP-10, monokine induced by gamma interferon, RANTES, eotaxin, MIP-1α, MIP-1ß, and MCP-1 levels using Luminex multicytokine immunobead assay. Intergroup comparisons were made using one-way analysis of variance or Kruskal-Wallis test. RESULTS: The tBUT was lower (P=0.048) and ocular surface staining (P=0.032) as well as OSDI scores (P=0.001) were higher in group 1 but not in groups 2 or 3 when compared with those in the control group. Tear cytokine levels were similar across all groups. None of the tear cytokine levels were elevated in CL wearers (groups 1 and 2) or those with MGD (groups 1 and 3) as compared to those in control subjects. CONCLUSION: Silicone hydrogel contact lens use with concomitant MGD is not associated with cytokine-driven ocular surface inflammation but may impact tear function leading to dry eye symptoms.